dc.creator | Bon, Corentin | |
dc.creator | Si, Yang | |
dc.creator | Pernak, Melanie | |
dc.creator | Barbachowska, Magdalena | |
dc.creator | Levi-Acobas, Eva | |
dc.creator | Cadet Daniel, Veronique | |
dc.creator | Jallet, Corinne | |
dc.creator | Ružić, Dušan | |
dc.creator | Đoković, Nemanja | |
dc.creator | Đikić, Teodora | |
dc.creator | Nikolić, Katarina | |
dc.creator | Halby, Ludovic | |
dc.creator | Arimondo, Paola B. | |
dc.date.accessioned | 2021-09-15T09:07:13Z | |
dc.date.available | 2021-09-15T09:07:13Z | |
dc.date.issued | 2021 | |
dc.identifier.issn | 1420-3049 | |
dc.identifier.uri | https://farfar.pharmacy.bg.ac.rs/handle/123456789/3954 | |
dc.description.abstract | Histone methyltransferase DOT1L catalyzes mono-, di-and trimethylation of histone 3 at lysine residue 79 (H3K79) and hypermethylation of H3K79 has been linked to the development of acute leukemias characterized by the MLL (mixed-lineage leukemia) rearrangements (MLLr cells). The inhibition of H3K79 methylation inhibits MLLr cells proliferation, and an inhibitor specific for DOT1L, pinometostat, was in clinical trials (Phase Ib/II). However, the compound showed poor pharmacological properties. Thus, there is a need to find new potent inhibitors of DOT1L for the treatment of rearranged leukemias. Here we present the design, synthesis, and biological evaluation of a small molecule that inhibits in the nM level the enzymatic activity of hDOT1L, H3K79 methylation in MLLr cells with comparable potency to pinometostat, associated with improved metabolic stability and a characteristic cytostatic effect. | |
dc.publisher | MDPI | |
dc.relation | Le Comitéde Paris de la Ligue contre la Cancer (project Epi-Med 2020-2021) to PBA. | |
dc.relation | Hubert Curien Partnership Project for collaboration France-Serbia 2020- 2022 (Program Pavle Savic 2020) to PBA and KN | |
dc.relation | EU COST CM1406 Epigenetic Chemical Biology program. | |
dc.rights | openAccess | |
dc.rights.uri | https://creativecommons.org/licenses/by/4.0/ | |
dc.source | Molecules | |
dc.subject | Bisubstrates | |
dc.subject | DOT1L | |
dc.subject | Histone methylation | |
dc.subject | HMT inhibitors | |
dc.subject | MLL rearranged leukemia | |
dc.subject | Rational drug design | |
dc.title | Synthesis and biological activity of a cytostatic inhibitor of MLLr leukemia targeting the DOT1L protein | |
dc.type | article | |
dc.rights.license | BY | |
dcterms.abstract | Ружић, Душан; Ђоковић, Немања; Ђикић, Теодора; Николић, Катарина; Бон, Цорентин; Си, Yанг; Пернак, Мелание; Барбацхоwска, Магдалена; Леви-Aцобас, Ева; Цадет Даниел, Верониqуе; Јаллет, Цоринне; Халбy, Лудовиц; Aримондо, Паола Б.; | |
dc.citation.volume | 26 | |
dc.citation.issue | 17 | |
dc.citation.rank | M22 | |
dc.identifier.wos | 000694318800001 | |
dc.identifier.doi | 10.3390/molecules26175300 | |
dc.identifier.scopus | 2-s2.0-85114232085 | |
dc.identifier.fulltext | https://farfar.pharmacy.bg.ac.rs/bitstream/id/9141/Synthesis_and_Biological_pub_2021.pdf | |
dc.type.version | publishedVersion | |